Congenital Myopathies

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Background

The first report of a congenital myopathy was in 1956, when a patient with central core disease (CCD) was described. Since that time, other myopathies have been defined as congenital myopathies, which have the following characteristics:

Hypotonia is the clinical hallmark of congenital myopathies. It presents in the neonatal period as head lag; lack of flexion of the hips, knees, and elbows; external rotation of the hips; diffuse weakness in facial, limb, and axial muscles; and reduced muscle mass.

The above features do not apply to all cases of congenital myopathy. Some cases have been reported as adult onset or as a progressive course. Some of the morphological alterations are not disease specific but are seen in various congenital myopathies or in other myopathic or nonmyopathic conditions.

A recent review article[1] divided the congenital myopathies based on genetic and morphological features into 4 main groups.

Myopathies with protein accumulation

Myopathies with cores

Myopathies with central nuclei

Myopathies with fiber size variation

With the advent of improved techniques such as electron microscopy, enzyme histochemistry, immunocytochemistry, and molecular genetics, the etiologies of many congenital myopathies are now well defined. This article focuses on the diseases with known mutations. The numerous rare congenital myopathies distinguished primarily based on a unique morphological feature on muscle biopsy are briefly discussed below (see Rare congenital myopathies).

Pathophysiology

In the common, well-described congenital myopathies, mutations have been identified in genes that encode for muscle proteins. The loss or dysfunction of these proteins presumably leads to the specific morphological feature on muscle biopsy samples and to the clinical muscle disease. The specific pathogenesis for each congenital myopathy is discussed below.

The same principle presumably leads to the morphological features determined by muscle biopsy in congenital myopathies whose genetic defects are not yet known.

Epidemiology

Frequency

International

The true incidence of congenital myopathies is unknown. In a series of 250 infants with neonatal hypotonia described by Fardeau and Tome, muscle biopsy performed before age 2 months revealed that only 14% had a congenital myopathy. Central nervous system (CNS) disease is the most common cause of congenital hypotonia.

The same authors documented 180 cases of congenital myopathy over 20 years. The types were as follows:

Mortality/Morbidity

Associated morbidity and mortality rates have considerable variability.

Sex

Both sexes are affected equally in most congenital myopathies since inheritance is usually autosomal recessive or autosomal dominant.

In X-linked forms, boys are affected almost exclusively, although occasional female carriers with clinical manifestations have been described.

Age

Congenital myopathies usually present in the neonatal period but can also present later in life (even into adulthood).

History

The following are congenital myopathies with known genetic mutations, categorized by their morphological features:

CENTRAL CORE DISEASE

Central core disease is due to a mutation in the ryanodine receptor (RYR1).

Typical presentation

Severe variant

Adolescent variant

Other presentations of ryanodine receptor mutations

Autosomal recessive and autosomal dominant inheritance have been described with several different presentations. Cores are not always present.

Multiminicore disease (see below)

Presentation is in infancy with generalized proximal > distal limb and axial weakness, bulbar, facial or respiratory weakness, external ophthalmoplegia, and joint abnormalities including hyperlaxity, contractures and arthrogryposis.

Congenital myopathy with cores and rods

Presentation is at birth with delayed motor milestones, decreased childhood motor abilities, and facial weakness.[3, 4] Weakness is slow or nonprogressive, with continued ability to walk into late adulthood. A severe presentation with prenatal akinesis, polyhydramnios, hypotonia at birth, respiratory failure, and death within 2 months has also been described.[5]

Nemaline myopathy with ophthalmoplegia

One case is reported with fetal akinesia, severe hypotonia and weakness, respiratory insufficiency and swallowing difficulty.[83] There was facial dysmorphism and ophthalmoplegia. Muscle pathology showed nemaline rods, but no central cores or minicores.

Centro nuclear myopathy

Seventeen of 24 patients with a histologic diagnosis of centronuclear myopathy but with no genetic diagnosis had a mutation in the RYR1 gene.[6] Reduced fetal movements and hypotonia at birth were common. Weakness was nonprogressive, and all children attained unsupported sitting and about half walked independently. Bulbar, facial, and extraocular muscle weakness was common. Malignant hyperthermia was not noted.

Congenital neuromuscular disease with uniform type 1 fibers (CNMDU1)

This is a rare disorder characterized by more than 99% type 1 muscle fibers without specific structural abnormality. Four of 10 patients with CNMDU1 were found to have a mutation in RYR. Clinical features included poor fetal movement, infantile hypotonia, poor suck, respiratory distress, proximal weakness, delayed motor milestones facial weakness, and skeletal deformity.[7]

Malignant hyperthermia

See Complications. About 70% of patients with malignant hyperthermia have a mutation in the RYR1 gene.[8] Malignant hyperthermia susceptibility 1 (MHS1) locus is the RYR1 gene. King-Denborough syndrome is included at this locus. Presentation is in childhood or adolescence usually with malignant hyperthermia. Non-progressive mild proximal weakness may be present. Mild dysmorphic facies and skeletal abnormalities such as short stature, pectus carinatum/excavatum, and scoliosis or kyphosis are often present.

Minimally or asymptomatic hyperCKemia

Presentation is usually as an adult with myalgia or fatigue. Malignant hyperthermia may occur.

NEMALINE (ROD) MYOPATHY

Nemaline (rod) myopathy can be caused by mutations in at least 9 different genes. General features of all nemaline myopathies include minimally progressive or nonprogressive proximal limb, bulbar, and facial weakness starting in the neonatal or childhood periods; hypotonia; and respiratory insufficiency, which is the most common cause of death. Skeletal deformities range from arthrogryposis in the severe congenital form to limb contractures, kyphoscoliosis, pectus excavatum, and rigid spine. Cardiomyopathy is rare but can be present early with congenital presentation, or it can be a late complication in childhood-onset or adult-onset cases. CNS disease is rare, but seizures have been reported in severe cases in the neonatal period.

Nemaline myopathy 1 (NEM1)

NEM1 is due to a mutation in the gene for α-tropomyosin 3 (TPM3). This is likely a rare cause (< 3%) of nemaline myopathy.[10] Autosomal dominant inheritance is usually due to a missense mutation and causes a moderate phenotype with onset between birth and 15 years. Weakness is diffuse and symmetric with slow progression often with need for a wheelchair in adulthood. Respiratory failure is common. Other features include kyphoscoliosis and a thin body habitus.

Autosomal recessive inheritance is usually due to a nonsense mutation causing a stop codon. Onset is at birth with moderate-to-severe hypotonia and diffuse weakness. In the most severe cases, death can occur before 2 years. Less severe cases have delayed major motor milestones, and these patients may walk, but often need a wheelchair before 10 years.

A single patient with TPM3 mutation and cap myopathy has been described (see below for NEM 4).

Nemaline myopathy 2 (NEM2)

NEM2 is due to a mutation in the gene for nebulin (NEB) and is likely the most common cause of nemaline myopathy. Inheritance in all cases has been autosomal recessive. Phenotypes are quite variable,[11] with all but the adult-onset form being described in a large series encompassing 55 families.[12]

The severe congenital form presents at birth with severe hypotonia and weakness. Lack of movement, poor suck and swallow, and respiratory failure are frequent findings. Death in utero due to fetal akinesia has been described. Arthrogryposis and severe respiratory failure are associated with early death that usually occurs within the first 2 years of life.

The intermediate congenital form presents with weakness in early childhood and is characterized by delayed motor milestones and contractures. Children with this form usually need a wheelchair or ventilatory support by age 10 years.

The typical (most common) congenital form presents within the first year of life with hypotonia, generalized limb weakness, facial weakness, feeding difficulty, and mild respiratory weakness. Features such as elongated face, tent-shaped mouth, high-arched palate, and retrognathia are common. Progression is static or very slow, and, after an initial rocky course, stabilization leads to an independent life.

The childhood-onset form presents with distal leg weakness in the late first or early second decade. Proximal muscles are involved later, and wheelchair dependency occurs in midlife.

The adult-onset form presents with symmetric proximal weakness in persons aged 20-50 years. Other features may include neck extensor weakness, respiratory insufficiency, or rapid progression.

Other forms include patients who do not fit any of the above presentations and can have cardiomyopathy, ophthalmoplegia, or an unusual distribution of weakness.

Nemaline myopathy 3 (NEM3)

NEM3 is due to autosomal dominant, autosomal recessive, or sporadic de novo mutations in alpha-actin (ACTA1). It is likely the second most common cause of nemaline myopathy (20-30%), and over represents the severe phenotype.

Presentation can be with any of the above forms. Autosomal dominant cases are usually mild, and recessive cases are usually severe. In a large series of 109 patients with nemaline myopathy 26% had a mutation in ACTA1.[13] More than 50% of patients had the severe congenital form of nemaline myopathy, although rare adult-onset cases have been described.

In a large series reporting previously published reports and unpublished data from the authors (Laing NG, et al.)[14] , 177 different mutations were described, 157 being missense, 133 being private, 74 arising de novo (most of these de novo dominant). Mutations occurred in 29% of the amino acid residues throughout α-actin. Only 21 autosomal dominant mutations were described, most having a mild phenotype. 17 autosomal recessive mutations were described, most causing a premature stop codon, complete absence of α-actin, and with a severe phenotype (rarely with a mild phenotype).

Mutations in ACTA1 can also cause nemaline myopathy with intranuclear rods.[15] Cases are most often sporadic but can be autosomal dominant. Presentation is likely similar to the typical nemaline myopathy, with 43% of cases having a severe congenital form, although adult-onset cases have been described. Other diseases described due to ACTA1 mutations include (1) actin filament aggregate myopathy[16] usually causing severe disease, (2) myopathy with core-like areas[17] , and (3) congenital fiber type disproportion (see below)

Nemaline myopathy 4 (NEM4)

NEM4 is due to an autosomal dominant mutation in the gene for β-tropomyosin (TPM2). It is a rare cause of nemaline myopathy.

Presentation is from infancy to childhood with hypotonia and moderate-to-severe proximal weakness with minimal or no progression. Major motor milestones are delayed but independent ambulation is usually achieved, although a wheelchair may be needed in later life.

Other problems can include feeding difficulties as an infant, facial weakness, long narrow face, high arched palate, kyphoscoliosis, and respiratory failure.

One consanguineous family with autosomal recessive inheritance has been described with a TPM2 mutation and Escobar syndrome[18] (thick skin folds keeping joints in a fixed position). Presentation was at birth with hypotonia, pterygia and arthrogryposis.

A mutation in TPM2 has also been described in cap myopathy.[19] This disease has only been described in 5 sporadic cases and in one family with dominant inheritance. Presentation is either congenital or childhood onset of hypotonia with facial and slowly progressive proximal weakness. Respiratory failure may result in death in teenaged years. Other features include a long narrow face and scoliosis. About 50% of muscle fibers showed a crescent-shaped peripheral cap that was granular in appearance on the modified GT stain and reacted strongly to NADH, phosphorylase, and periodic acid-Schiff, but not to myosin ATPase. On electron microscopy (EM), the caps were filled with abnormally arranged myofibrils, which lacked thick filaments.

Distal arthrogryposis has also been described as due to a mutation in TPM2.[20] Presentation is at birth with flexion contractures of hands and feet.

Nemaline myopathy 5 (NEM5)

NEM5 is due to an autosomal recessive mutation in the gene for troponin T1 (TNNT1) and has been described only in the Old Order Amish.[21] Onset is in the first few months of life with hypotonia, proximal weakness, and jaw and limb tremors that resolve over a few months. Death occurs before age 2 years due to respiratory failure. Other features include shoulder and hip contractures and pectus carinatum.

Nemaline myopathy 6 (NEM6)

NEM6 is due to a mutation in Kelch repeat and BTB/POZ domains-containing protein 13 (KBTBD13).[22] Presentation is in childhood with inability to run or jump. Slow movements are noted in most patients. Proximal and neck weakness is prominent. Progression is slow.

Nemaline myopathy 7 (NEM7)

NEM7 is due to an autosomal recessive mutation in the gene for cofilin-2 (CFL2) and has been described in only one family.[23] Presentation is at birth with hypotonia and generalized weakness. Major motor milestones are delayed, but independent ambulation is achieved.

Nemaline myopathy 8 (NEM8)

NEM8 is due to an autosomal recessive mutation in the gene for Kelch-like family member 40 (KLHL40).[82] This is a common form of severe nemaline rod myopathy, accounting for 20% of all cases screened and 28% of patients in the Japanese population.

Patients present at birth with a severe syndrome. The majority have fetal akinesia or hypokinesia. Respiratory failure, facial weakness, facial dysmorphism, dysphagia, contractures and diffuse weakness occur in over 90%. In one series, ventilation was needed in 38% and gastrostomy tube was needed in 54%. Other features included ophthalmoparesis and pathological fractures. Many patients died within the first 6 months of birth, although some lived into the second decade.

Nemaline myopathy (This mutation is not yet listed in OMIM as a cause of nemaline rod myopathy)

An autosomal recessive mutation in Kelch-like family member 41 (KLHL41) can cause nemaline rod myopathy.[84] A severe phenotype due to a frameshift mutation presents with decreased fetal movements, breech presentation, arthrogryposis and skeletal abnormalities. Death is before 3 months of age. In contrast, missense mutations result in mild to moderate weakness, contractures, and mild skeletal deformities with life into teenage years. Wheelchair and respiratory support are needed in some, but other patients remained ambulatory without assistive devices.

CENTRONUCLEAR (CNM)/MYOTUBULAR MYOPATHY

Three different presentations (ie, severe X-linked form, autosomal recessive form, autosomal dominant form) have been described.

CNM; Autosomal dominant mutations in dynamin 2 (DNM2)[24, 25]

CNMX; X-linked mutations in myotubularin (MTM1)[30]

CNM2; Autosomal recessive mutations in amphiphysin 2 (bridging integrator 1; BIN1)[31]

CNM; Autsomal recessive compound heterozygoze mutations in ryanodine receptor (RYR1)

CNM3; Autosomal dominant mutations in myogenic factor 6 (MYF6)[85]

CNM4; Autosomal dominant mutation in coiled-coil domain containing protein 78 (CCDC78)[86]

CNM; Autosomal recessive mutations in titin (TTN)[87]

MULTIMINICORE DISEASE

The classic and most common phenotype presents with spinal rigidity, axial weakness, scoliosis, and early respiratory impairment. It is most often due to a mutation in the gene for selenoprotein N (SEPN1) (Congenital Muscular Dystrophy). Mutations in RYR1 are also a common cause (see above). However, several other genes have been found to cause similar phenotypes and muscle pathology and together mutations in SEPN1 and RYR1 account for < 50% of cases.

SEPN1 (Selenoprotein N, 1)

Mutations in selenoprotein N, 1 cause 4 overlapping phenotypes: multiminicore disease, congenital muscular dystrophy with rigid spine, congenital fiber-type disproportion (CFTD), and desmin-related myopathy with Mallory body–like inclusions.

Eleven patients from eight families with a mutation in selenoprotein N were described[32] and have the classic phenotype.

A second phenotype that is similar to the classic phenotype with the added finding of ophthalmoplegia is most often due to dominant or recessive mutations in the gene for the ryanodine receptor (see above for central core disease). Ophthalmoplegia has been reported in patients with a mutation in the selenoprotein N gene.

A third mild phenotype presents with pelvic girdle weakness and is also often due to a mutation in the ryanodine receptor which can be dominant or recessive(see above for central core disease). Onset may be in infancy or childhood and other features include minimal or mild respiratory involvement, but without respiratory failure as well as joint laxity, hip dislocation, and arthrogryposis. Patients may also present in adulthood with myalgias and hyperCKemia.[9] These patients and at risk family members should be screened for malignant hyperthermia.

Lastly, a fourth phenotype presents antenatally with arthrogryposis. Other findings include head, face, trunk, and limb dysmorphic features; proximal muscle weakness; and respiratory insufficiency. Scoliosis or kyphoscoliosis is severe.

Rare causes of muscle pathology showing multicores or minicores

Mutations in SECISBP2 lead to multisystem selenoprotein deficiency including in SEPN1.[90] Patients have a multisystem disorder including early onset of axial and proximal muscle weakness, stiff spine, respiratory difficulty and fatigue. Other features include developmental delay, azoospermia, cutaneous photosensitivity, Raynaud’s, hearing loss, impaired T-lymphocyte proliferation abnormal mononuclear dell cytokine secretion and telomere shortening.

SCAD (Short-chain acyl-CoA dehydrogenase) deficiency;[88] neonatal onset patients had hypotonia, developmental delay, speech delay, myopathy, lethargy and feeding difficulties. Later onset patients had ophthalmoplegia, ptosis, weakness and scoliosis.

EMARDD (Early-onset myopathy with areflexia, respiratory distress and dysphagia) due to a mutation in multiple epidermal growth factor-like domains 10 (MEGF10);[89] presentation before 1 year with severe proximal and distal weakness, hypotonia, respiratory impairment, scoliosis and joint contractures with stabilization in teenage years.

Titin (LGMD2J) gene mutation was reported to cause a minicore-like disease with early onset myopathy and fatal cardiomyopathy in 2 consanguineous families.[91] Presentation was before 1 year of age with symmetric proximal, distal and facial weakness, ptosis, joint and neck contractures, spinal rigidity and progressive dilated cardiomyopathy with concomitant ventricular rhythm disturbances and sudden cardiac death.

Myosin – Cardiac b heavy chain (MYH7) mutations most often cause myosin storage myopathy/hyaline body myopathy (see below), but a variant syndrome causes multi-minicore disease with variable cardiac involvement.[92] Presentation is in childhood with slowly progressive weakness, proximal or distal, facial weakness, scapular winging, contractures, spinal rigidity and variable degrees of cardiorespiratory impairment later in life. Sudden cardiac death may occur.

Congenital fiber-type disproportion (CFTD)

This term was initially coined to describe a group of infants with small type 1 muscle fibers and the clinical syndrome of hypotonia and diffuse weakness that may improve with age. Other clinical features can include facial, bulbar, and respiratory weakness; short stature; low body weight; multiple joint contractures; scoliosis; long, thin face; and high-arched palate. Ophthalmoplegia, cardiac disease, and mental retardation are rare. Mutations in several genes can cause CFTD.

CFTD 1

Mutations in the gene for ACAT1 account for fewer than 10% of cases.[35] Presentation is at birth with severe weakness most prominent in proximal, truncal, facial, and respiratory muscles. Severe feeding difficulties are present, and invasive ventilation is often needed. Most patients die due to progressive respiratory failure before 4 years of age.

CFTD 3

Mutations in the gene for selenoprotein N account for fewer than 10% of cases.[34] Selenoprotein N mutations also cause congenital muscular dystrophy with spinal rigidity (Congenital Muscular Dystrophy), multiminicore disease, and desmin-related myopathy with Mallory body-like inclusions. Presentation is before 1 year of age with hypotonia and poor head control.

CFTD 4

Mutations in TPM3 may account for up to 25% of cases.[33] Onset is usually before 1 year of age but may be in young adulthood.

CFTD 5

Mutations in the gene for RYR1 may be a common cause of CFTD, possibly up to 10% of cases.[36] In 4 of 7 families with small type 1 fibers as the main histologic feature, clinical features consistent with CFTD and no mutation in ACAT1 or TPM3, a compound heterozygous mutation was found in RYR1.

Note that there are many other causes of type 1 fiber hypotrophy including other congenital myopathies (nemaline rod myopathy, centronuclear/myotubular myopathy, multiminicore myopathy), muscular dystrophies (eg, Emery-Dreifuss muscular dystrophy, LGMD2A, congenital muscular dystrophy with spine rigidity due to mutations in selenoprotein N), polymyositis, perinatal asphyxia, leukodystrophies, spinal muscular atrophy, arthrogryposis, and Pompe disease.

Myosin storage myopathy

Myosin storage myopathy (hyaline body myopathy) is due to a mutation in the myosin heavy chain 7 gene (MYH7) and is autosomal dominant or sporadic.

Onset usually is in infancy or childhood but with variable penetrance; some patients present in adult life or may even be asymptomatic in their 40s.[37]

Weakness can be proximal, proximal and distal, or scapuloperoneal in distribution. Progression is minimal or very slow (rare cases may have more rapid progression).

Occasional cardiac arrhythmias may be present.

The same mutation may present with variable phenotypes as exemplified by one mutation (Leu1793Pro) shown to present with neonatal hypotonia, adult onset proximal weakness and isolated neonatal cardiomyopathy.[38]

One family was described with histologic findings of CFTD in younger patients while in an older patient biopsy there were aggregates of slow myosin heavy chains.[39]

The disease is allelic with Laing early adult-onset distal myopathy type 3, and patients with myosin storage myopathy may have overlapping features of finger, toe, and ankle extensor weakness.

Other rare presentations of MYH7 mutations include multiminicore disease or congenital fiber type disproportion.[94]

Mutations in MYH7 also cause hypertrophic cardiomyopathy (CMH-1), dilated cardiomyopathy (CMD-1S), and familial left ventricular non compaction.

Sarcotubular myopathy

Inheritance is autosomal recessive. Onset is in childhood in most but in mid-adult life in some, with mild-to-moderate proximal weakness and mild facial weakness. Other features include muscle atrophy, contractures, exercise-induced myalgias, and scapular winging. This disease is allelic with LGMD 2H (Limb-Girdle Muscular Dystrophy) making it likely that these two diseases are the same disorder.[40]

Reducing Body myopathy

Reducing body myopathy has been shown to be due to a mutation in Four and a half LIM domain 1 (FHL1) on the X-chromosome. Several syndromes harbor the same mutation. Overlapping features include progressive weakness, rigid spine, scapular winging and contractures. Cardiomyopathy and respiratory involvement are seen in most subtypes. However, there are also differences in age of onset, distribution and severity of weakness and rate of progression.[41]

Spheroid body myopathy

Spheroid body myopathy due to a mutation in the myotilin gene has been found in one large kindred.[47] This myopathy can be considered a myofibrillar myopathy/ desminopathy since aggregates include desmin. Mutations in myotilin also cause LGMD type 1A (Limb-Girdle Muscular Dystrophy.

Presentation varied from childhood to the eighth decade, most often with proximal weakness that slowly progressed as well as dysarthric speech.

Swallowing difficulties, loss of ambulation, and need for respiratory support occurred in a few individuals.

Rare congenital myopathies

In the most recent edition of the textbook Myology (2004), the remaining congenital myopathies are divided into "probable," meaning several familial cases have been reported, and "possible or doubtful," meaning fewer than 10 cases have been reported.

Probable congenital myopathies

Possible congenital myopathies

Causes

One will notice that the same mutation can cause varying presentations.

Central core disease

CCD is usually transmitted in an autosomal dominant fashion with variable expression and incomplete penetrance (rare autosomal recessive and sporadic cases) and is almost always due to a mutation in the ryanodine receptor 1 (RYR1). CCD has been reported in a few families with familial hypertrophic cardiomyopathy due to a mutation in the cardiac myosin b-heavy chain.

Mutations (most often missense) in RYR1 can cause CCD, as described above, malignant hyperthermia susceptibility, or both. Mutations in RYR1 can also cause core-rod myopathy, multiminicore myopathy, and rare cases of centronuclear myopathy.

RYR1 is the calcium channel on the sarcoplasmic reticulum (SR) that releases calcium into the muscle cytoplasm during excitation-contraction coupling, thereby allowing calcium to interact with muscle contractile proteins. It exists as a tetrameric structure and associates with several other proteins including the dihydropteridine receptor, calmodulin and calsequestrin. Ordered 2-dimensional arrays are formed at the junctional terminal cisternae, in which each of the 4 subunits in every other RYR1 tetramer is physically coupled to a dihydropteridine receptor, and each RYR1 tetramer is physically coupled to 4 other tetramers.

Over 300 mostly missense (96%) mutations have been described. Mutations have been found throughout the entire length of RYR1, although 3 relative hot spots have been described.

One hypothesis proposed to explain malignant hyperthermia suggests that it results from abnormal repetitive Ca2+ cycling, characterized by spontaneous Ca2+ release and reuptake triggered by volatile anesthetics, stress, or elevated temperature.[48]

Other proposed mechanisms for malignant hyperthermia include inter-domain unzipping of RYR subunits, changes in RYR redox status, increased rate of Ca2+ entry into the sarcoplasmic reticulum lumen following adrenergic stimulus, changes in RyR phosphorylation status and elevated enzymatic Ryr function.

A hypothesis to explain phenotypic variability, variable penetrance and core formation is based on nonuniformity of the Ca2+ release unit.[48] The Ca2+ release unit refers to the two-dimensional array of RyR1 molecules described above.

Because CCD is typically associated with heterozygous missense mutations, both wild type and mutant subunits are expressed. Random combination of subunits into RyR1 tetramers would produce 16 possible arrangements with 6 variants (homotetrameric wild type channels [1], homotetrameric mutant channels [1] and heterotetrameric channels in arrangements 3:1 [4]; 1:3 [4], 2:2 (side by side-[4]); 2:2 (diagonal-[2]).

The random association of different subunits within each tetramer followed by the random association of the 16 different types of tetramers within each Ca2+ release unit would set the stage for nonuniformity of Ca2+ release. This could also lead to nonuniformity of contraction among sarcomeric domains and subsequently to nonuniformity within myofibrils, myofibers, and muscle fasciculi ultimately, resulting in variable degrees of weakness that characterize RyR1-related myopathies.

Cores could be formed due to discordant contraction between adjacent myofibers. This would cause physical stress that could lead to tearing and shearing between myofibrils as well as displacement of mitochondria and the sarcotubular system. Eventually, small foci of damage would coalesce and manifest as cores.

Patients with autosomal recessive inheritance may have a more severe phenotype often with ophthalmoplegia. Mutations are spread throughout the RyR1 protein.[49] In several of these patients, a heterozygous missense mutation was expressed on a background of a second nontranscribed allele (epigenetic silencing). In these patients, a dramatic reduction in RyR1 protein levels occurred (patients with typical CCD have normal protein levels).

Pathology

Central cores are single, well-circumscribed, central, circular areas that extend the length of most type 1 muscle fibers. See the image below.



View Image

Central core disease, nicotinamide adenine dinucleotide (NADH) stain. In the central core, mitochondria and oxidative enzymes are absent. Cores are al....

Central cores are devoid of SR and mitochondria and have reduced or absent oxidative enzymes, such as nicotinamide adenine dinucleotide (NADH), succinate dehydrogenase (SDH), and cytochrome oxidase (COX), and are therefore best visualized as negative staining areas when muscle tissue is reacted for these enzymes. Reduced staining is also usually seen when muscle sections are reacted for phosphorylase, glycogen, and myosin ATPase.

Electron microscopy often shows disruption of the contractile apparatus within the cores.

Structured cores maintain the sarcomeric structure, which is lost in unstructured cores because of muscle fiber degeneration.

Cores often immunostain for a variety of molecules, including desmin, RYR1, and g-filamin.

Other common histochemical features, aside from the central cores, include type 1 muscle fiber predominance, variable muscle fiber size, and increased internal nuclei.

Nemaline (rod) myopathy

Seven different mutations have been described, all but one (KBTBD13) in components of the muscle thin filament. Mutations likely impair the proper formation, maintenance, or function of thin filaments, which results in accumulation of sarcomeric components and formation of nemaline bodies (rods) and the associated muscle weakness. No clear associations exist among specific mutations, mode of inheritance, and clinical severity, although mutations in ACTA1 likely account for about 50% of severe congenital disease.

NEM1 is due to mutations in the gene for α-tropomyosin (TPM3)

Autosomal dominant or recessive mutations in the gene for α-tropomyosin 3 (TPM3) cause NEM1. TPM3 mutations more commonly cause congenital fiber size disproportion. Tropomyosins are a family of actin-binding coiled coil proteins that help to regulate calcium-dependent muscle contraction. Multiple isoforms exist, with three stiated muscle isoforms; α-tropomyosinfast (TPM1), β-tropomyosin (TPM2), and α-tropomyosinslow (TPM3). In muscle the heterodimers α-tropomyosinslow -β-tropomyosin (slow twitch) and α-tropomyosinfast -β-tropomyosin (fast twitch) are most common.

In human and animal studies of a dominant mutation of TPM3 a number of functinoal defects were noted. There was reduced affinity for F-actin, reduced formation of preferred α/β heterodimers in favor of α/α heterodimers, destabilization of the coiled coil, impaired binding to tropomodulin and reduced sensitivity of isometric force production to activating calcium.[50] ,[51] ,[52]

In autosomal recessive cases in which no functional α-tropomyosin is present, altered ratios of the remaining sarcomeric proteins may be sufficient to cause the formation of rods.

NEM2 is due to mutations in the gene for nebulin (NEB)

Autosomal recessive mutations in the gene for nebulin (NEB) cause NEM2, likely the most common cause of nemaline myopathy. Nebulin is a large protein that extends the whole length of the thin filament. It has a highly repetitive structure (repeats have an α-helical structure) and can bind up to 200 actin molecules. It is present in skeletal and cardiac muscle. It is required for the proper assembly of thin filaments and for the maintenance of thin filament length and contractile function. It is also likely responsible for proper periodicity of the troponin/tropomyosin complex. Multiple isoforms exist, differing in the C-terminal structure, which binds α-actinin in the Z-disk and nebulin likely plays a role in Z-disk assembly.

Small deletions and duplications causing frameshifts and point mutations causing stop signals or altered splicing are more common than missense mutations.[12] No mutational hotspots exist. It is expected that nonsense and frameshift mutations cause mRNA instability or truncated nebulin molecules while missense mutations likely disrupt the binding of actin to nebulin or affect the secondary structure of nebulin.

A clear genotype-phenotype correlation does not exist, but, in milder disease, it is likely that several normal isoforms are expressed.

NEM3 is due to mutations in the gene for α-actin (ACTA1)

Mutations in ACTA1 cause NEM3 and account for 15-25% of nemaline rod myopathies. α-actin is present in skeletal muscle but not cardiac muscle. It makes up 10-20% of muscle protein. The actin monomer, G-actin (has binding site for myosin) polymerizes to form F-actin. Two strands of F-actin combine in a double helix as part of the thin filament. F-actin binds to other thin filament proteins including nebulin, tropomyosins and troponins and most importatnly binds myosin during muscle contraction.

Most mutations are missense and spread throughout the gene. Autosomal dominant mutations exert a dominant negative effect and autosomal recessive mutations that result in no functional actin both cause cytoplasmic rods, suggesting that multiple mechanisms are responsible for disease manifestations. ACTA1 mutations may have one or more effects; increase or decrease 1) polymerization into F-actin, 2) the sliding speed of actin filaments, 3) calcium regulation or 4) the strength of binding to α-actinin.[14]

In autosomal dominant disease, there are likely abnormalities in folding, polymerization, or aggregation of mutant actin, whereas, in autosomal recessive disease, altered ratios of sarcomeric proteins during development or turnover of the thin filament are sufficient to form rods. Therefore, nemaline rods may result from either changes in normal stoichiometry of sarcomeric proteins or due to the presence of mutant α-actinin.

The degree of sarcomeric disruption, as seen on electron microscopy, correlates with disease severity such that, in general, the most severely affected patients have the most myofibrillar disorganization.

NEM4 is due to mutations in the gene for β-tropomyosin (TPM2)

Autosomal dominant mutations in TPM2 are a rare cause of nemaline rod myopathy. Abnormal tropomyosin-actin interactions resulting in reduction in force generation, increased activation of myosin ATPase and destabiliztion of the coiled coil structure have been reported.

Mutations have also been associated wtih distal arthrogryposis and pterygia suggesting that β-tropomyosin may have a unique role during fetal development, particulary in distal muscles.

NEM5 is due to mutations in the gene for troponin T1 (TNNT1)

Three troponin subunits act as a complex to bind calcium and either block or unblock the myosin-binding site on actin. Troponin T binds to tropomyosin, troponin I inhibits actin-myosin interaction and troponin C binds calcium. Mutations in different isoforms of all of the three subunits cause distal arthrogryposis and cardiomyopathy.

Autosomal recessive mutations in the gene for troponin T1 (TNNT1) cause NEM5 in the Older Order Amish.[21] The mutation causes a premature stop codon. The truncated protein removes the principal site of binding to troponin C and troponin I. It is hypothesized that the mutation results in mutant message undergoing nonsense-mediated decay or an unstable protein that is degraded. There is therfore a complete loss of troponin T1. Early compensation at birth may be due to fetal transcription of TNNT2 and TNNT3.[53]

NEM6 is due to a mutation in KBTBD13

Autosomal dominant mutations in KBTBD13 cause NEM6. KBTBD13 protein localizes to the cytoplasm of skeletal and cardiac muscle. Over 60 proteins of the BTB/Ketch family have been identified. Functions include cytoskeletal modulation, regulation of gene transcription, ubiquitination, cell migration and myofibril assembly.[22]

Pathological changes in muscle biopsies include numerous rods near Z-disks, type 1 fiber predominance and hypertrophy, and unstructured cores devoid of oxidative enzyme activity.[22]

NEM7 is due to a mutation in cofilin-2 (CFL2)

Autosomal recessive mutation in the gene for cofilin-2 (CFL2) cause NEM7 in one family.[23] Cofilins are actin-modulating proteins that act to depolymerize F-actin and inhibit the polymerization of G-actin. Cofilin-2 is a muscle-specific isoform that exerts its effect on actin, in part, through interactions with tropomyosin.

NEM8 is due to a mutation in Kelch-like family member 40 (KLHL40).

Autosomal recessive mutations, often with consanguinity, are common in severe cases of nemaline rod myopathy.[82] KLHL40 is a member of the kelch-repeat-containing protein superfamily. Members of this family have a wide range of functions which generally involve protein-protein interactions.KLHL40 is more abundant in fetal skeletal muscle than in adult muscle and localizes to the A-band. Muscle pathology from affected patients showed numerous small rods, many requiring EM for visualization.KLHL40 immunostaining is reduced or absent in muscle of patients harboring a mutation. Knockdown of KLHL40 in Zebrafish resulted in disruption of myofibers, widened Z-disks, aggregates containing a-actinin (Z-disk protein) and loss of movement. It is thought to likely play a role in muscle development and function.

NEM due to a mutation in Kelch-like family member 41 (KLHL41).

Autosomal recessive mutations in KLHL41 can cause nemaline rod myopathy with frameshift mutations causing a severe phenotype and missense mutations causing a more moderate phenotype.[84] Muscle pathology showed sarcoplasmic rods, EM evidence of severe myofibrillar disarray and KLHL41 reduction or absence by immunostaining. Knockdown of KLHL41 diminished motor function, nemaline bodies and myofibrillar disorganization.

Patholgy

Rods, the pathologic hallmark of nemaline rod myopathy, are only visible on modified Gomori trichrome (GT) stain as dark red/purple structures, as shown below.



View Image

Nemaline rod myopathy, Gomori trichrome (GT) stain. Dark blue structures are seen only with this stain. They contain Z disk material, including alpha-....

Usually, the rods are sarcolemmal but may be intranuclear.

Derived from the Z-disk, rods are often in continuity with the Z-line. They are composed of primarily α-actinin (the primary component of Z-lines) as well as other Z-line and thin filament proteins, including actin, telethonin, and myotilin. Rods presumably form secondary to contractile protein (especially thin filament) dysfunction.

Rods may be seen in many other diseases including inflammatory myopathies, muscular dystrophies, mitochondrial myopathies, HIV myopathy, chronic renal failure, spinal muscular atrophy, Charcot-Marie-Tooth disease, and monoclonal gammopathy.

Other common pathologic features include type-1 fiber predominance or atrophy.

Centronuclear/myotubular myopathy

Centronuclear/myotubular myopathy can be due to several different mutations, but all affected proteins have a role in membrane trafficking or in the maintenance of skeletal muscle fiber orignization, especially in the postitioning of nuclei.[54]

MTM1 mutations (CNMX)

X-linked myotubular myopathy is due to a mutation in the myotubularin (MTM1) gene. Point mutations (missense, nonsense, and splice site), as well as small or large insertions and deletions, have been found throughout the gene. A clear genotype-phenotype correlation does not exist, but most nonsense and splice site, as well as some missense mutations in conserved residues, result in a severe phenotype, and many missense mutations or deletions have a mild phenotype. Myotubularin is ubiquitously expressed in the nucleus of most cells.

Myotubularin is a lipid phosphatase whose main action is to dephosphorylate phosphoinositide-3-phosphate. Phosphoinositides are specialized lipids that target localization of proteins to various subcellular organelles and are important in membrane trafficking.

Myotubularin interacts with proteins with the SET domain that are important in epigenetic mechanisms of gene regulation. Myotubularin may serve as a link between genetic regulatory proteins and signaling pathways involved in vesicular trafficking of substrate necessary for myoblast fusion.

In myotubularin knockout mice, muscle development occurs normally, but a myopathy develops suggesting that the absence of myotubularin affects muscle maintenance, not muscle formation.

DNM2 mutations (CNM)

Autosomal dominant centronuclear myopathy is due to a mutation in dynamin 2 (DNM2). Dynamins are large GTPases that are involved in organelle fission events. Dynamin 2 has been implicated in endocytosis, and a likely hypothesis is that endocytotic function is disrupted due to mutations in dynamin 2. Other actions of dynamin that may play a role in disease pathogenesis include actin assembly, cytokinesis, and regulation of centrosomal function. Dynamin 2 mutations can also cause a CMT 2 phenotype with axonal neuropathy and clinical features that overlap with autosomal dominant centronuclear myopathy.

BIN1 mutations (CNM2)

Autosomal recessive centronuclear myopathy is due to a mutation in amphiphysin 2 (bridging integrator 1; BIN1). Amphiphysins are involved in endocytosis, signal transduction, transcriptional regulation, and vesicle fusion. Amphiphysin 2 mutations have been shown to impair T-tubule function, formation or maintenance. BIN1 protein binds to DNM2 protein and mutations in BIN1 may disrupt this binding or binding to T-tubules.[31]

MYF6 mutations (CNM3)

Autosomal dominant centronuclear myopathy is due to a mutation in myogenic factor 6 (MYF6).[85] MYF6 appears to be involved in terminal differentiation of myotubes. Muscle biopsy shows a significant increase in the number of central nuclei.

CCDC78 mutations (CNM4)

Autosomal dominant centronuclear myopathy is due to a mutation in coiled-coil domain-containing protein 78 (CCDC78).[86] CCDC78 is expressed in skeletal muscle, enriched in the perinuclear region and triad, and found in intracellular aggregates in patient muscle. Muscle biopsy shows high proportion of central nuclei, type 1 fiber predominance, desmin positive aggregates and core-like areas.

TTN mutaions (CNM)

Autosomal recessive centronuclear myopathy is due to mutation in titin (TTN).[87] Titin mutations also cause LGMD2J. Muscle biopsy in cases with centronuclear myopathy show prominent internal and central nuclei, type 1 fiber hypotrophy and predominance, myofibrillar and sarcomeric disorganization. There is increased titin degradation and truncated titin protein in patient muscle tissue.

Pathology

The pathologic hallmark of all myotubular myopathies (X-linked and autosomal) is the predominance of type-1 fibers with large, centrally placed nuclei, as shown below. However, it is not known how any of the above mutations cause the pathologic abnormality. In DNM2 -related centronuclear myopathy the additional finding of radiating sarcoplasmic strands from the central nuclei is often present, often best seen on NADH staining.[55]



View Image

Centronuclear myopathy, hematoxylin and eosin stain. Note the numerous, centrally placed nuclei. Normal nuclei are at the periphery of the muscle fibe....

Most fibers are small and round and resemble fetal myotubes, which normally have central nuclei. The central part of the fiber contains an abundance of mitochondrial enzymes and glycogen, but lacks myosin ATPase activity.

Type-1 muscle fiber hypotrophy is usually present. A variable degree of endomysial fibrosis and fatty replacement is present, often depending on time course and severity with more severe abnormalities increasing with age.

Internal nuclei (not necessarily centrally placed) are more common in patients with RYR1 mutations.[55]

Necklace fibers - fibers with internalized nuclei in a basophilic ring just below the sarcolemma - have been described in patients with MTM1 and DNM2 mutations.[56, 57]

Immunohistochemical studies have shown persistence of fetal vimentin and desmin and of neonatal myosin, giving further credence to the maturational arrest of muscle fibers.

Muscle fibers with central nuclei can also be seen in denervation, muscle fiber regeneration, and any chronic myopathy.

Multiminicore disease

Most cases are inherited in an autosomal recessive fashion, but sporadic cases have also been reported.

Mutations in the selenoprotein N gene (SEPN1) have been found in several families with a typical severe presentation and autosomal recessive inheritance (~30% of mulitminicore disease). Mutations in SEPN1 also cause congenital muscular dystrophy with rigid spine (see Congenital Muscular Dystrophy), and it has been proposed that these disorders be called SEPN-related myopathies. The role of selenoprotein N in causing multiminicore disease is unknown, but its expression is developmentally regulated in muscle. More than 20 mutations have been described, with more than half resulting in a truncated protein that is likely degraded. Selenoprotein N may play a role in redox reactions of membrane proteins, including the ryanodine receptor, and lack of this protein may result in oxidative stress leading to abnormal receptor function.[58] In multiminicore disease due to a mutation in the Selenocysteine insertion sequence-bindingprotein 2 (SECISBP2) gene, the reducedsynthesis of all selenoproteins including selenoprotein N likely accounts for the similar pathology.[90]

Mutations in the ryanodine receptor 1 (RyR1) have been noted in some cases of multiminicore disease with autosomal recessive (rarely autosomal dominant) inheritance. Mutations in RyR1 more commonly cause central core disease with or without malignant hyperthermia. The reason why mutations in the same protein result in different phenotypes is not known. Potential defects may be related to instability of the RyR1 macromolecular complex or to a reduction in the number of RyR1 receptors on the sarcoplasmic reticulum.[58]

How mutations in the rare causes of multiminicore disease result in similar muscle pathology is unknown.

Pathology

The pathologic hallmark of the disease is the presence of multiple areas of sarcomeric disorganization associated with diminished mitochondrial oxidative activity.

The disease is best identified with muscle reacted for oxidative enzymes NADH, SDH, and COX. Reduced staining for myosin ATPase, glycogen, and phosphorylase may also be noted.

Multiminicores differ from central cores in the following ways: occur in type 1 and type 2 fibers; poorly defined limits; vary in orientation to muscle fiber axis; multiple lesions within one muscle fiber; and smaller in size, never extending the length of the muscle fiber.

Other features may include increased endomysial connective tissue, increased internal nuclei, and type-1 muscle fiber predominance.

Multiminicores may be present as a nonspecific feature in many other diseases, including mitochondrial diseases, CNS disorders, and denervation.

Congenital fiber-type disproportion

Congenital fiber-type disproportion (CFTD) has as the main pathologic hallmark small type-1 muscle fibers. The original definition requires that type-1 fibers are 12% smaller in diameter than type-2 fibers, although often the difference is closer to 50%. Other common features are type-1 fiber predominance and reduced or absent type-2B fibers.

CFTD 1

Autosomal dominant mutations in ACTA1 are a rare cause of CFTD. Mutations in the gene for α-actin are a common cause of nemaline myopathy. It has been shown that CFTD mutant α-actin is unable to properly interact with tropomyosin, leaving tropomyosin in the "switched off" position, thereby not allowing actin to interact with myosin. Furthermore, the sarcomeric disruption common in α-actin mutations that cause severe nemaline myopathy is not seen in patients with severe weakness due to CFTD. These data have lead to the hypothesis that the α-actin mutations that cause CFTD result in disturbed sarcomeric function rather than structure.[59]

CFTD 3

Autosomal recessive mutations in the gene for selenoprotein N are a rare cause of CFTD. Mutations in the gene for selenoprotein N also cause multiminicore disease and congenital muscular dystrophy with rigid spine. The reason why different mutations cause different muscle pathologies is not clear, but clinical syndromes overlap with most patients having a rigid spine and respiratory insufficiency.[32]

CFTD 4

The most common cause is due to autosomal dominant or sporadic (likely de novo autosomal dominant) mutations in the gene for α-tropomyosin 3 (TPM3). Mutations in TPM3 are a rare cause of nemaline myopathy, but they are a common cause of CFTD.[33] The reason why certain mutations cause rod formation while others cause CFTD is not known. Biopsy samples showed a predominance of type-1 fibers (83%) that were 72% smaller than type-2 fibers. Some mutations can cause CFTD in some family members and rod formation in others.

CFTD 5

Autosomal dominant mutations in the gene for b-tropomyosin (TPM2) are a rare cause of CFTD.[93] Mutations in TPM2 more commonly cause rod myopathy. Interestingly mutations in TPM2 and TPM3 can cause CFTD, nemaline rod myopathy and cap myopathy suggesting that these may be related entities.

Autosomal recessive mutations in RYR1 may be the second most common cause of CFTD. All patients had one null mutation and one missense mutation. Biopsies showed type 1 fibers 51-84% smaller than type 2 fibers. Why RYR1 mutations cause CFTD in some patients and central core disease in others is unknown. Although none of the patients with CFTD had a family history of malignant hyperthermia, standard precautions are prudent.[36]

Myosin storage myopathy (hyaline body myopathy)

Mutations in the slow/β-cardiac myosin heavy-chain gene (MYH7) have been reported in sporadic or autosomal dominantly inherited cases. Mutations in MYH7 also cause Laing early adult-onset distal myopathy type 3 and cases of familial hypertrophic cardiomyopathy, dilated cardiomyopathy and left ventricular noncompaction.

Pathology

Hyaline bodies are subsarcolemmal areas, mostly in type-1 muscle fibers, that are devoid of sarcomeres and react with myosin ATPase but not oxidative enzymes or glycogen. They are pink on hematoxylin and eosin (H&E) staining, and pale green with modified GT staining. They are composed of granular and filamentous material in continuity with adjacent thick myosin filaments. The hyaline bodies immunostain intensely with antibodies against the slow myosin heavy chain and have been proposed to result from myofibrillolysis of the mutated slow myosin heavy chain within type-1 muscle fibers.

Type-1 muscle fiber predominance is common.

Interestingly, some patients with a mutation in MYH7 do not have hyaline bodies on muscle biopsy sample.

Sarcotubular myopathy

This myopathy is due to a mutation in Tripartite-motif containing gene 32 (TRIM32).

Inheritance is autosomal recessive, and all cases have the same mutation (D487N) that causes limb-girdle muscular dystrophy 2H (Manitoba Hutterite dystrophy).

TRIM 32 is an E3 ubiquitin ligase that is expressed in muscle. It interacts with myosin and can ubiquinate actin. E3 ubiquitin ligase activity is not abolished due to this mutation. Nevertheless, altered ability to ubiquinate may result in accumulation of proteins that are not tagged for degradation by the proteosomal system.[60]

EM reveals numerous small, membrane-bound vacuoles that appear to originate from the sarcotubular system and have reactivity to T-tubule and SR-associated proteins, most often affecting type-2 muscle fibers.

Reducing body myopathy

This is an X-linked dominant disease due to a mutation in Four and a half LIM domain 1 (FHL1).[41]

The LIM domain is a cysteine-rich double zinc-finger structure that bind zinc ions for protein stabilization. FHL proteins scaffold cytoskeletal and cell signaling complexes and help regulate gene transcription. FHL proteins are thought to be involved in myoblast migration and elongation as well as sarcomere formation through binding of myosin-binding protein C. In adult myofibers, FHL1 through the calcineurin signaling pathway helps to regulate myoblast fusion, skeletal muscle hypertrophy, and oxidative fiber-type shifting.

Cardiomyopathy is common in patients with FHL1 mutations and FHL1 plays multiple roles in the heart including modulation of conduction through interaction with the potassium channel KCNA5, regulation of cardiac hypertrophy through binding components of the MAPK signaling pathway and detection of mechanical stretch through interaction with the elastic N2B region of titin.

Why different mutations in FHL1 cause different syndromes is unknown, but mutations causing the more severe reducing body myopathy are often in exons 4/5 whereas mutations in the less severe Emery-Dreifuss muscular dystrophy are in exons 5-8.

In most patients FHL1 levels are reduced suggesting that loss of normal protein function via reduced FHL1 protein expression of impairment of protein-partner binding may also be important in disease pathogenesis.

Pathology

EM reveals numerous subsarcolemmal, non–membrane-bound aggregates composed of granulofilamentous and tubular structures, which stain pink with H&E and purple with the modified GT stain. The name "reducing body" was coined when the inclusions were found to have reducing activity when salts are applied to the muscle fiber.

Immunohistochemical analysis has shown features similar to that of aggresomes including perinuclear location and the presence of desmin, ubiquitin, and luminal endoplasmic reticulum chaperone GRP78. Wild-type and mutated FHL1 is also present in the inclusions and the aggregation of these (and other as yet unidentified) proteins may play a role in the pathogenesis of the disease through a toxic gain of function.

Spheroid body myopathy

This myopathy is due to an autosomal dominant mutation in the gene for myotilin (titin immunoglobulin domain protein; TTID), which also causes LGMD type 1A and a myofibrillar myopathy.

Spheroid bodies are more common in type-1 muscle fibers and devoid of enzymatic activity. Electron microscopy shows fine filaments and streaming of Z disks. Immunohistochemical studies show the presence of desmin and ubiquitin, similar to what is found in many myofibrillar myopathies.

Myotilin binds actin and is thought to be involved in stabilization of actin bundles and anchorage of thin filaments at the Z disk.

Laboratory Studies

Creatine kinase level

Creatine kinase (CK) level is either in the reference range or mildly elevated in all of the congenital myopathies.

It can be elevated moderately in central core disease (CCD) and may also be elevated in asymptomatic carriers of the ryanodine receptor mutation in CCD.

If the CK level is very high, other disorders such as Duchenne-Becker or limb-girdle muscular dystrophy, should be considered.

Other Tests

Electromyography and nerve conduction studies

Electromyography (EMG) and nerve conduction studies (NCSs) should be performed in all patients in whom a congenital myopathy is suspected.

In the differential diagnosis, rule out other diseases such as spinal muscular atrophy, congenital myasthenia, and hereditary neuropathy.

In congenital myopathy, NCS findings are normal and EMG findings are either normal or show the typical small-amplitude, narrow-duration motor unit potentials (MUPs) that are seen in myopathies. Fibrillations and positive sharp waves are rare.

Electrocardiography (ECG)

Cardiac disease may be prominent in nemaline myopathy or, at times, in other congenital myopathies. Obtain ECG when considering these diagnoses.

Procedures

Muscle biopsy

Obtain a muscle biopsy in all patients in whom a congenital myopathy is suspected. Pathological examination should be performed at a center whose staff has expertise in muscle pathology.

Other causes of weakness need to be ruled out. In addition, the morphologic characteristics necessary to make the diagnosis need to be established.

Ultrastructural examination of muscle is often necessary, since several of the pathologic features are based on the EM appearance of muscle.

Medical Care

No specific treatment is available for any of the congenital myopathies, but aggressive supportive care is essential to preserve muscle activity, to allow for maximal functional ability, and to prolong life expectancy.

The primary concerns affecting prognosis are preventing and correcting skeletal abnormalities (eg, scoliosis, foot deformities, contractures) to maintain ambulation, and to prevent or delay the development of respiratory insufficiency.

Respiratory failure due to diaphragmatic weakness can occur at any age and may be independent of the degree of limb weakness.

A restrictive pattern on pulmonary function tests (PFTs) may be apparent before the onset of symptoms.

Early symptoms of nocturnal hypoxia can include poor sleep, nightmares, morning headache, daytime sleepiness, and weight loss.

All patients should have baseline PFTs that are repeated in at least yearly intervals.

Treatment options include chest physiotherapy, manually assisted cough, early treatment of respiratory infections, noninvasive ventilation, and tracheostomy combined with permanent ventilation.

Skeletal abnormalities are frequent complications of patients with a congenital myopathy.

Treatment to prevent contractures includes aggressive use of passive stretching, exercise, bracing, and surgical release procedures; these allow the patient to remain independent for as long as possible.

The development of scoliosis or kyphosis may impede standing, sitting, walking, and respiratory function. Bracing or surgical correction with spinal fusion are treatment options.

The special concern of malignant hyperthermia in patients with central core disease (CCD) is discussed in Complications.

As for other hereditary myopathies, a team approach, including a neurologist, pulmonologist, cardiologist, orthopedic surgeon, physiatrist, physical/occupational therapist, orthotist, and counselors, ensures the best possible therapy.

Surgical Care

Orthopedic surgery may be needed to help correct or prevent contractures, foot deformities, and scoliosis. A gastrostomy tube may be needed for newborns who have persistent feeding difficulties, although many neonates improve and can tolerate bottle-feeding after a few months of gavage feeding.

Consultations

See the list below:

Diet

While no dietary restrictions are indicated in the myopathies, the diet should be tailored to the caloric needs of the patient. This may include restricting calories, especially in children with minimal mobility.

Activity

As mentioned above, one of the main goals of treatment is maintaining ambulation and functional ability with the aggressive use of physical therapy and bracing. Children should attend school either in regular classes or in classes designed to meet their specific physical needs. Regular exercise helps with cardiovascular fitness and general well-being.

Further Outpatient Care

In patients with a congenital myopathy, assess the following at least yearly:

Further Inpatient Care

Neonates with a congenital myopathy with severe weakness and hypotonia may need prolonged hospitalization for respiratory insufficiency and feeding difficulties. If the disease is nonprogressive, support can often be successfully withdrawn as symptoms improve.

Older children may need admission for surgical care or cardiopulmonary complications.

Complications

Patients with central core disease (CCD) (less frequently with multicore disease) are inclined to develop malignant hyperthermia. However, since the precise diagnosis may not be known, precautions should be taken in all patients with a presumed diagnosis of congenital myopathy. General anesthesia usually triggers a full-blown episode, but excessive heat, neuroleptic drugs, alcohol, or infections may trigger milder episodes.

If surgery is required, these patients (and their relatives) should avoid inhaled anesthetics (except nitrous oxide) and succinylcholine.

Signs and symptoms of malignant hyperthermia include the following:

Appropriate treatment includes the following:

Cardiac involvement can occur in patients with congenital myopathies, especially nemaline myopathy, CCD, and multiminicore disease.

Pulmonary insufficiency can occur in any form of congenital myopathy that presents with severe neonatal hypotonia. It is more common or more severe in nemaline myopathy, X-linked and autosomal myotubular/centronuclear myopathy, multiminicore disease, and reducing body myopathy. This is especially important to assess before surgery since postoperative respiratory failure can occur.

Skeletal deformities, including contractures and scoliosis, are common in patients with most of the congenital myopathies.

Obstetric complications during childbirth are uncommon in mothers with congenital myopathy. However, neonatal complications can include polyhydramnios; decreased fetal movements; or complications related to fetal distress, abnormal presentation, failure to progress, or prematurity.

Prognosis

The prognosis depends on the form of congenital myopathy.

Severe disease often results in death in the neonatal period. Less severe disease can result in lifelong disability. Milder forms of congenital myopathy may result in only minor disability with a relatively normal life expectancy.

Patient Education

Genetic counseling is often helpful to assist patients with family-planning decisions. However, definitive prenatal diagnosis is only possible if a disease-causing mutation has been identified. Genetic counseling is especially important for families of patients with CCD to avoid unexpected cases of malignant hyperthermia in asymptomatic relatives.

Author

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alnylam Pharmaceuticals<br/>Received income in an amount equal to or greater than $250 from: Alnylam Pharmaceuticals; GLG.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Kenneth J Mack, MD, PhD, Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic

Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD, Attending Neurologist, Children's National Medical Center

Disclosure: Have stock (managed by a financial services company) in healthcare companies including AbbVie, Allergan, Celgene, Cellectar Biosciences, Danaher Corp, Mckesson.

Additional Contributors

Robert J Baumann, MD, Professor of Neurology and Pediatrics, Department of Neurology, University of Kentucky College of Medicine

Disclosure: Nothing to disclose.

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Tubular aggregates, nicotinamide adenine dinucleotide (NADH) stain. Cytoplasmic collections of membranous tubules (derived from the sarcoplasmic reticulum) can be present in various myopathies, including myopathy with tubular aggregates, hypokalemic periodic paralysis, malignant hyperthermia, myotonia congenita, and ceratin toxic myopathies.

Central core disease, nicotinamide adenine dinucleotide (NADH) stain. In the central core, mitochondria and oxidative enzymes are absent. Cores are also present on cytochrome oxidase and succinate dehydrogenase (SDH) stains.

Nemaline rod myopathy, Gomori trichrome (GT) stain. Dark blue structures are seen only with this stain. They contain Z disk material, including alpha-actinin and tropomyosin.

Centronuclear myopathy, hematoxylin and eosin stain. Note the numerous, centrally placed nuclei. Normal nuclei are at the periphery of the muscle fiber.

Central core disease, nicotinamide adenine dinucleotide (NADH) stain. In the central core, mitochondria and oxidative enzymes are absent. Cores are also present on cytochrome oxidase and succinate dehydrogenase (SDH) stains.

Nemaline rod myopathy, Gomori trichrome (GT) stain. Dark blue structures are seen only with this stain. They contain Z disk material, including alpha-actinin and tropomyosin.

Centronuclear myopathy, hematoxylin and eosin stain. Note the numerous, centrally placed nuclei. Normal nuclei are at the periphery of the muscle fiber.

Tubular aggregates, nicotinamide adenine dinucleotide (NADH) stain. Cytoplasmic collections of membranous tubules (derived from the sarcoplasmic reticulum) can be present in various myopathies, including myopathy with tubular aggregates, hypokalemic periodic paralysis, malignant hyperthermia, myotonia congenita, and ceratin toxic myopathies.